Opioids.pdf

Opioids “I’ll die young but its like kissing God”  Lenny Bruce 1925-1966  John Belushi  Chris Farley  Philip Seymour Hoffman  Sid Vicious  https://www.youtube.com/watch?v=g- 9KyxMtGXg  Opioids  Theophrastus in...

Opioids “I’ll die young but its like kissing God”  Lenny Bruce 1925-1966  John Belushi  Chris Farley  Philip Seymour Hoffman  Sid Vicious  https://www.youtube.com/watch?v=g- 9KyxMtGXg  Opioids  Theophrastus in 300 BC Papaver somniferum  Opium  Juice of the poppy Smoked Opium Wars, 19th century Injected  Wars  Heroin  Highly addictive and Abused 1.9m (all opioids) 600K heroin in US, Often die in 3rd decade (19K/y up to 50K) Opioid Epidemic  Opioids  Morphine:  Prototypical opiate agonist  Isolated in 1803 by Friedrich Serturner Morpheus god of dreams  Opioids are the most potent and efficacious analgesics.  Analgesic agents Endogenous peptides Natural (opiates): Morphine, codeine Semi-synthetic: oxycodone, diacetylmorphine (heroin) Synthetic: Fentanyl, methadone  Opioid receptors  Three classical receptors  µ MOP  κ KOP  δ DOP  Οrphan Receptor (OFQ or Nociceptin) Little to no affinity for conventional opioid ligands Regulates MOP activity: analgesia, tolerance, reward  GPCRs Pertussis toxin sensitive G-protein (Go Gi)  Opioid receptor mechanism  Activation of receptor causes:  ↓ Adenylyl cyclase activity (postsynaptic)  Activation of receptor- operated K+ currents (Postsynaptic)  ↓ Voltage gated Ca +2 currents (presynaptic)  Mechanisms act to block or reduce pain transmission.  Opioid receptors  Throughout the nervous system, GI, adrenal medulla  Effective analgesics—non-selective agents  Efficacy is mediated primarily through the µ receptors.  Endogenous Opioid peptides:  Enkephalins  Leu-enkephalin  Met-enkphalin  Endorphins  Alpha-neoendorphin  Beta-neoendorphin  Betah-neoendorpin  Dynorphins  Dynorphin-A  Dynorphin-B  Nociceptin  Endomorphins (1+2)  Function:: Agonism of End. Lig affin. µ Supraspinal + spinal analgesia—Euphoria endorph >enkeph >dynorph ↓ respiration—sedation—↓GI transit tolerance, dependence δ Supraspinal + spinal analgesia—Euphoria Enkeph>>endorph+dynoph tolerance κ Supraspinal + spinal analgesia—Dysphoria Dynoph>>endorph+enkeph Sedation—psychotomimetic effects ↓ GI transit ↑ diuresis  Adaptation  Functional consequences to agonist activation is due to:  Decreased Adenylyl cyclase (post-synaptic inhibition)  Increased K+ channel activity (post-synaptic inhibition)  Decreased Ca+2 channel activity (pre-synaptic inhibition)  Also there are links to other 2nd messenger systems:  IP3, DAG, MAP kinases, PLC etc.  Chronic exposure to opioids leads to adaptations within all of these systems.  This results in: tolerance, dependence, withdrawal.  Definitions  Tolerance:  The reduced efficacy of a drug with repeated use.  Dependence:  Complex changes in an organism leading to altered homeostatic balance which consequently results in a withdrawal syndrome.  Tolerance and Dependence  Seen in all patients  Not predictors of addiction or abuse (23% of people who try Heroin become dependent)  Addiction in small percent of people exposed, usually after months and addiction is molecularly distinct (epigenetic changes) from T+D Rates are 21-22% misuse, best is ~8-12% addicted Prescription opioids are diverted, those addicted to opioids 4% goto heroin  Should we withhold opioid analgesics because of this concern?  Definitions  Withdrawal:  Physical and psychological syndrome caused by the abrupt cessation of a drug  Addiction:  Behavioral pattern which is characterized by the compulsive use of a drug and an overwhelming involvement in its procurement and use. Intense drive with procurement/use Difficult to predict who will become  ADHD, history of addiction, adolescents  Some heritability ( 35-40% of risk)  When the drug is removed T+ D resolve w/in wk but addiction stays (increasing risk of OD)  Reward  Basic:  Mesolimbic dopamine pathway  From ventral tegmental area (VTA) to the nucleus accumbens (NAcc) which projects to the prefrontal κ and δ are weakly activated by morphine cortex  Underlies the euphoria and pleasurable feelings of opioids  Receptors are highly concentrated in the NAcc.  Euphoria is rapid especially with lipophilic drugs like heroin  Analgesic effects of opioids  Pain  Protective mechanism  In fight or flight response pain needs to be reduced so that we can still react. Endogenous opioids facilitate pain tolerance  Modulation of these pathways with exogenous compounds like morphine is therefore adventitious for analgesia  Analgesic effects of opioids  Pain  Nociceptive pain: stimulation of nociceptors along intact neural pathways Responds well to opioids  Neuropathic pain: pain caused by damage to neuronal structures, involving neural supersensitivity. Responds poorly to opioids (what can we use) May respond to higher dose  Results of Opioid agonism  The µ agonists have many CNS effects:  Analgesia: both sensory and emotional  Euphoria: floating sensation reduced stress and anxiety  Sedation: Drowsiness and sleep can be produced. Other species are actually opposite like cats, horses, cows and pigs.  Respiratory depression: brainstem respiratory centers (caution in Head Trauma). Occurs at therapeutic doses It is influenced by the degree of sensory input.  Stronger input less respiratory depression  When sensory input decreases the depression increases.  Therapeutic uses of opioids  Analgesia for moderate to severe pain  Postoperative pain control (short term)  Terminal illness (amphetamines may enhance) Self dosing vs. fixed interval Sustained release  Weak agonists for less severe pain  More potent for moderate to severe  Combined with NSAIDs additive Hydrocodone + ibuprofen/acetominaphen/aspirin patients have variable responses to opioids Might be used around the clock  Therapeutic Uses  Spinal analgesia  Epidural or intrathecal (reduced dose)  reduce the unwanted side effects like respiratory depression from systemically given opioids.  Effective pain relief for 12-24 hours Nausea, vomiting, itching, respiratory depression Respiratory depression can emerge so an opioid antagonist should be on hand, Naloxone.  Therapeutic uses of opioids  Acute pulmonary edema/left ventricular failure  IV morphine is beneficial though its mechanism is not clear  Cough (Antitussive)  Opioid receptors are in the medullary cough center Codeine and dextromethorphan (non-opiod σ) Suppression by opioids can allow accumulation of secretions in the airways.  Diarrhea  Receptors in the ENS µ and κ mostly  Anesthesia (minimize CV effects)  Premedication, sedative, anxiolytic and analgesic  Fentanyl (high dose) as a primary component fast onset and short duration. (plus midazolam)  Opioid agonism  CNS effects:  Miosis: parasympathetic pathways Little or no tolerance makes this effect useful in diagnosis Atropine can block this effect.  Convulsions: inhibition of GABA inhibition Antagonist to treat – anticonvulsants may not work  Muscle rigidity: IV of lipid soluble agents like Fentanyl.  Nausea and vomiting Receptors in the chemoreceptor trigger zone  Hypothalamus heat regulation and hormone dysregulation  Opioid agonism  Non-CNS effects  Cardiovascular Bradycardia via CNS Hypotension can occur with cardiovascular stress Meperidine can cause tachycardia (antimuscarinic)  Gastrointestinal effects Constipation ENS/CNS—reduces motility  Renal depressed function/antidiuresis  Uterus May prolong labor  Pruritus Especially parenteral—Histamine release Strong Opioid agonists  Morphine (MSContin)  Hydromorphone (Dilaudid)  Oxymorphone (Numorphan)  Diacetylmorphine (heroin)  Methadone (Dolophine)  Meperidine (Demerol)  Fentanyl (Duragesic, Sublimaze)  Weak Opioid agonists  Codeine  Oxycodone (OxyContin)  Hydrocodone (Vicodin; w/acetomin.)  Diphenoxylate (Lomotil)  Loperamide (Imodium)  Tolerance develops to agonist effects  High tolerance  Moderate  Analgesia  CV Bradycardia  Euphoria/dysphoria  Little/none  Sedation  Miosis  Respiration  Constipation  Antitussive  Convulsant  Nausea/vomiting  Antidiuresis  Tolerance develops to agonist effects  Crosstolerance is usually not complete but does occur.  Opioid rotation  So when switching to increase analgesia with another agent you potentially will see increased respiratory depression too. Titrate up slowly Morphine-hydromorphone-methadone  Block tolerance Ketamine or receptor selectivity (δ), cytokines (IL- 1, TNF-a etc.) Morphine (MS Contin, Avinza etc.)  IM, SubQ, oral extended release, depo prep. (+ antagonist)  Potency of all agents is compared to Morph  Long term use for pain management  Precautions  Crosses BBB/placental and into breast milk  Asthma/ respiratory depression  Head injury use caution  Can cause histamine release  Hydromorphone (Dilaudid)  IV, IM oral  ½ life 2-3hrs  15’ to analgesia IV dose  Shorter duration unless ER  Extended release Palladone removed due to Etoh interaction caused elevated release  Methadone (Dolophine)  Oral, IV, SubQ, rectal  Analgesia 10-20’ parenteral, 30-60’ orally  Better oral absorption than morphine  Very long elimination 24-52 hrs makes this an ideal agent for reducing the unwanted withdrawal effects after the removal of opioids.  Potent µ agonist + NMDA antag and Reuptake inhibitor.  Uses:  Opioid use disorder treatment ()  Difficult to treat pain (neuropathic)  Opioid rotation  Fentanyl (Sublimaze, Duragesic)  Transdermal, transmucosal, parenteral  Potent synthetic µ receptor agonist 100 xs more than morphine  High lipid solubility: rapid onset short duration  Indications:  Anesthesia induction  Epidural Combined with Bupivacaine a local anesthetic for epidural nerve block.  Severe breakthrough pain with cancer Patients who have developed tolerance to opioids may respond to high dose transmucosal fentanyl (Actiq)  Substitutes in many drugs: heroin, amphetamine Carfentanil (1000x morph) Sufentanil (Sufenta), more potent derivatives. Lead to many deaths  Heroin  Metabolized to morphine  Precursors are more rapidly absorbed than morphine so faster onset  Street heroin has a varying degree of purity.  Adding other agents like fentanyl!!  Codeine (Codicaps FM)  Formulations: oral  Tylenol w/ codeine  Greater oral availability (↓ 1st pass metab)  Hepatic metabolism converts to morphine  10% is de-methylated to morphine (analgesia) 10% of Caucasians cannot convert so no analgesia  Indications:  mild to moderately severe pain  Persistent Cough Hydrocodone (Vicodin, Zohydro)  Oral + acetaminophen (rule change)  analgesia  Tussionex: cough suppressant formulation  Extended Release problem with Zohydro (hyslinga w/ deterrent)  abuse deterrent (Vantrela ER) 2/13/17 (9 opioids with deterrent)  Weak-moderate agonist  Indications:  Mild to Moderate pain Dental pain headache  Cough suppression  Oxycodone (OxyContin, Roxicodone Percodan)  Stronger than hydro- similar combos and uses; w/ H20 gel forms: also plus antagonists  Tramadol (Ultram)  Oral, IM, IV  Ultracet—w/ acetaminophen  Synthetic opioid like codeine that is a weak agonist at µ receptors  Also inhibits reuptake of Norepinephrine/Serotonin  Indications:  Used short term for moderate to severe pain  Similar to meperidine for labor pain  Opioids with mixed action These agents can be full agonists, partial agonists or antagonists at different opioid receptors. Receptor Potency actions Nalbuphine Full agonist κ High (Nubain) Antagonist µ Pentazocine Partial agonis µ Moderate (Talwin) Full agonist κ Buprenorphine Partial agonist µ HIGH (Buprenex) Antagonist κ Butorphanol Strong agonist κ High (Stadol) Partial agonist µ A partial agonist or an antagonist can precipitate a withdrawal syndrome if given to a patient who has previously been taking an agonist.  Nalbuphine (Nubain)  Parenteral  Equianalgesic/potent to morphine  agonist at κ and an antagonist at µ receptors.  It can cause respiratory depression but this effect reaches a “ceiling” where further respiratory depression does not occur with higher doses. Analgesia too.  Respiratory depression caused by other agents can be reversed with Nubain due to this effect.  Can cause withdrawal in an opioid dependent pt.  Indications  Mild to moderate analgesia  Anesthesia supplement  Buprenorphine (Buprenex, Sublocade, Probuphine)  Sublingual or parenteral, transdermal subdermal implant (1 + 6 month)  Partial µ agonist with slow rate of dissociation. Less euphoria, ceiling  κ antag, δ ag and partial agonist orphanin  Pain and Used in addiction treatment regimens  Suboxone: this is a combined formulation with the opioid antagonist naloxone (Narcan)  Kappa is blocked…this might help with stress induced drug relapse (k is upreg in addiction)  So there is partial activation of µ and block of κ resulting in a more euthymic response than naloxone  Agonist Drug interactions  Sedative hypnotics: ↑ CNS depression (respiratory depression can be fatal)  Antipsychotics: ↑ sedation, variable respiratory effects, accentuation of cardiovascular effects.  MAO inhibitors: Contraindicated can lead to hyperpyretic coma.  Low doses of amphetamines dramatically increase analgesia and euphoria  Contraindications  Head injury  CO2 levels increase with resp. depression causing vasodilation in the brain increasing pressures  Pregnancy:  Dependence in fetus leading to neonatal withdrawal  Resp. depression, hepatic and renal dysfunction  In pain management combining a weak/partial agonist can inhibit analgesia of a strong agonist.  https://www.youtube.com/watch?v=g- 9KyxMtGXg  Typical toxicity syndrome:  Shallow and slow respiration  Miosis—pin point pupils  Bradycardia, hypothermia  stupor or coma  Pale, blue or cold skin  Treatment  Support respiration  Antagonist like naloxone reversal in 1-2 min.  Antagonists  Naloxone (Narcan)  Non selective all true opioid receptor subtypes (not σ)  Poor oral efficacy (nasal spray and injection)  Used primarily for reversal of opioid overdose. Patients wake right up.  Short duration 1-2 hrs (caution can relapse)  Titration for epidural to alleviate nausea/itching  Abuse deterrent formulations  Naloxegol (Movantik) peripheral for OIC  Antagonists  Naltrexone (ReVia, Depade)  Good oral absorption, Long action 48 hrs.  Added to morphine to prevent abuse, not absorbed unless tampered with, crushing etc  Potentiate analgesia with agonists and might reduce tolerance and dependence combined with oxycodone  Low doses alone for analgesia Low level block stimulates the release of endorphin  Combined with bupropion for weight loss  Methylnaltrexone (Relistor) subQ, OIC